ESPEYB18 5. Bone, Growth Plate and Mineral Metabolism Translational highlights (4 abstracts)
5.11. Crtap and p3h1 knock out zebrafish support defective collagen chaperoning as the cause of their osteogenesis imperfecta phenotype
F Tonelli , S Cotti , L Leoni , R Besio , R Gioia , L Marchese , S Giorgetti , S Villani , C Gistelinck , R Wagener , B Kobbe , I A K Fiedler , D Larionova , B Busse , D Eyre , A Rossi , P E Witten & A Forlino
Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy.
Matrix Biol. 2020 Aug;90:40–60 Abstract: https://pubmed.ncbi.nlm.nih.gov/32173581/
In brief: Mutations in 3-hydroxylation complex genes CRTAP and P3H1 cause osteogenesis imperfecta type VII and VIII, respectively. However, the pathogenic mechanism by which these mutations cause disease remains unclear. This study points to a defective chaperone role of the 3-hydroxylation complex as the main cause of the skeletal phenotypes.
Comment: Collagen type I in fibrillar collagens undergoes 3-hydroxylation of proline residues, a rare post translational modification with still unknown role. The endoplasmic reticulum (ER) complex composed of cartilage associated protein (CRTAP), prolyl 3-hydroxylase 1 (P3H1) and prolyl cis/trans isomerase B are responsible for 3-hydroxylationof proline in collagen type I, and has both an enzymatic and chaperon function. Its mutation cause moderate to lethal recessive forms of osteogenesis imperfecta (OI) with impaired levels of α1(I)3Hyp986, namely OI type VII and VIII. However, what causes the bone phenotype in these OI patients when 3-hydroxylation complex is altered is still unclear.
As collagen type I with 3-hydroxylated proline is absent in wild type zebrafish, the authors used this model to study the role of the chaperone function of the ER complex. CRISPR/Cas9 was used to generate zebrafish knock outs for crtap and p3h1 and extensive molecular, morphological, biochemical and histomorphometric analyses demonstrated that mutant fish exhibit reduced size, body disproportion, delayed mineralization, as well as altered vertebral bone morphology and skeletal deformities, resembling features in human OI patients. Mutant fish also showed impaired bone properties such as reduced size, thickness and bone volume. At intracellular level collagen type I was overmodified and retained in ER, inducing an ER enlargement, whereas it created disorganized fibers with altered diameter in the surrounding extracellular matrix. Taken together, these findings suggest that the complex has an important chaperone role in collagen folding and that disruption of this function is the main pathogenic mechanisms by which mutation in CRTAP and P3H1 causes phenotypes of OI type VII and VIII, respectively.
Volume 18
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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